FR3065370A1 - USE OF A RESVERATROL ASSOCIATION TO FIGHT THE SIGNS OF SKIN AGING - Google Patents

Abstract

The invention relates to the cosmetic use of a combination of (i) resveratrol or one of its derivatives and (ii) betaine, or a composition containing said combination in a physiologically acceptable medium, for controlling against the signs of aging of the skin. It also relates to a cosmetic treatment method using said combination and compositions containing

Description

® FRENCH REPUBLIC

NATIONAL INSTITUTE OF INDUSTRIAL PROPERTY © Publication number:

(to be used only for reproduction orders)

©) National registration number

065 370

53526

COURBEVOIE

©) Int Cl ⁸ : A 61 K8 / 37 (2017.01), A 61 K8 / 44, 31/215, 31/205, A 61 Q 19/00, A 61 P 17/00, C 07 C 69/017, 229/12

A1 PATENT APPLICATION

©) Date of filing: 24.04.17. © Applicant (s): CAUDALIE IP— GB and PRESIDENT (30) Priority: AND FELLOWS OF HARVARD COLLEGE— US. ©) Inventor (s): THOMAS MATHILDE, THOMAS BER- TRAND and SINCLAIR DAVID. (43) Date of public availability of the request: 26.10.18 Bulletin 18/43. (56) List of documents cited in the report preliminary research: Refer to end of present booklet (© References to other national documents ©) Holder (s): CAUDALIE IP, PRESIDENT AND FEL- related: LOWS OF HARVARD COLLEGE. ©) Extension request (s): ©) Agent (s): LLR.

FR 3 065 370 - A1 (34) USE OF A RESVERATROL-BASED COMBINATION TO FIGHT AGAINST THE SIGNS OF AGING SKIN.

©) The invention relates to the cosmetic use of a combination (i) of resveratrol or one of its derivatives and (ii) of betaine, or of a composition containing said association in a physiologically acceptable medium, to fight the signs of aging skin.

It also relates to a cosmetic treatment process using said combination and compositions containing

The present invention relates to a cosmetic treatment method for combating the signs of aging of the skin and integuments, and improving the appearance of the skin. It also relates to compositions containing a synergistic association for maintaining the energy of the skin, and the synthesis of its essential constituents, as well as the use of said association.

The skin consists of two compartments, one superficial, the epidermis, and a deeper, the dermis, which interact. The human epidermis is mainly composed of three types of cells, which are the keratinocytes, which are very predominant, the melanocytes and Langerhans cells. Each of these cell types contributes by its own functions to the role of the skin in the body, and in particular to protection against external aggressions.

The epidermis is conventionally divided into a basal layer of keratinocytes constituting the germinal layer of the epidermis, a so-called thorny layer consisting of several layers of polyhedral cells arranged on the germinal layers, one to three so-called granular layers consisting of flattened cells containing distinct cytoplasmic inclusions, keratohyaline grains and finally the stratum corneum (or stratum corneum), consisting of a set of layers of keratinocytes at the terminal stage of their differentiation called corneocytes.

The dermis provides the epidermis with solid support. It is also its nourishing element. It is mainly made up of fibroblasts and an extracellular matrix composed mainly of collagen, elastin and a substance, called the fundamental substance. These components are synthesized by fibroblasts. There are also leukocytes, mast cells or tissue macrophages. Finally, the dermis is crossed by blood vessels and nerve fibers.

Cohesion between the epidermis and the dermis is ensured by the dermoepidermal junction.

Mitochondria are organelles found in most cells, where they play an essential role in energy processes and cellular respiration. With age, mitochondrial dysfunction contributes to the appearance of signs of aging, especially of the skin.

The number or functioning of mitochondria can decrease with age.

Furthermore, it is known that the collagen and elastin present in the skin can also decrease over time in an individual, causing the appearance of skin signs such as wrinkles, fine lines or loss of elasticity of the skin.

The phenomena of aging, whether of intrinsic or extrinsic origin, are natural normal phenomena, which occur in healthy individuals. However, there is still a need for a large number of men and women to improve the appearance of their skin or their integuments and to reduce or delay the signs associated with aging of the skin.

Resveratrol and its derivatives are antioxidant agents useful in cosmetics, giving good results in the fight against the signs of skin aging.

Resveratrol derivatives have been described in application WO 99/03816, for therapeutic, cosmetic or dietetic applications.

Application FR 3 017 289 describes compositions with high direct antioxidant power containing polyphenol derivatives and vitamin C.

However, there is always a need to find new active agents, or combination of active agents, which are effective in combating the signs of aging of the skin or of the integuments.

Unexpectedly, it has been found in the context of the present invention that betaine can combat certain signs of aging, by acting on different effects of age on the skin. All these effects are also obtained with resveratrol, which acts synergistically with betaine.

This is why the subject of the present invention is a method of cosmetic treatment of the signs of aging of the skin or of the integuments comprising a step of application, on the skin covering or its appendices, of a combination (i) of resveratrol or one of its derivatives and (ii) betaine or one of its derivatives, or a composition containing them in a cosmetically acceptable medium.

Another subject of the invention is the use of a combination (i) of resveratrol or one of its derivatives and (ii) of betaine or one of its derivatives, as an agent for combating the signs of aging of the skin or appendages, in particular topically.

The invention thus relates to the cosmetic use of a combination (i) of resveratrol or one of its derivatives and (ii) of betaine or one of its derivatives, or of a composition containing said association in a physiologically acceptable medium, to fight against the signs of aging of the skin.

The uses and methods according to the invention are, unless it is stipulated differently, of cosmetic, non-therapeutic nature; they essentially have an aesthetic purpose.

The subject of the invention is also a composition, useful for the implementation of the cosmetic treatment process, containing a combination (i) of resveratrol or one of its derivatives and (ii) of betaine, in a physiologically acceptable medium. , in particular a cosmetically acceptable medium.

Betaine, or tri-methyl glycine, is conventionally used in cosmetics as a formulation excipient, surfactant or antistatic. It has also been proposed as a humectant or as a hair conditioner.

FR2877843 relates to the use of betaine to combat stresses of water or thermal origin.

WO 91/18588 describes the use of betaine to reduce the irritation of the skin induced by cosmetic compositions. WO 2010/043769 also relates to the use of betaine to protect the skin from irritation.

DE102011089558 proposes the use of a mixture of betaine and urea derivatives to strengthen the barrier function of the skin.

However, to the knowledge of the applicant, an effect of betaine has never been described to combat the signs of aging.

Surprisingly, it has now been demonstrated that betaine significantly increases the mitochondrial mass in skin cells, in particular the skin cells of elderly subjects.

For the purposes of the present invention, the term “elderly subjects” means human individuals aged over 30 years, in particular over 40 years, and advantageously aged over 50 years, or even over 60 years.

It is known that aging in mammals and more particularly in humans, is accompanied by alterations in the mitochondria. In addition, the amount of mitochondria in cells decreases with age.

Mitochondria produce energy in cells by contributing to the production of ATP through β-oxidation, the Krebs cycle and the respiratory chain as part of oxidative phosphorylation. Aging is accompanied by a decrease in activity in the respiratory chain, which results in a decrease in ATP production. This decrease was estimated at 8% per decade.

ATP is also essential in numerous processes essential for good cellular functioning, and in particular for the maintenance of protein synthesis activities including the synthesis of proteins from the extracellular matrix.

Mitochondrial dysfunctions and in particular the decrease in respiratory activity in the skin cells can thus promote a loss of softness, flexibility and / or elasticity of the skin, the formation of wrinkles or fine lines, a dull complexion and / or inhomogeneous, and a loss of radiance or transparency of the skin.

Betaine is also capable of stimulating the metabolism of the mitochondria and more particularly of restoring the energy of the cell.

This activity is obtained synergistically for a combination of betaine and resveratrol, or its derivatives.

By synergy is meant that the effect obtained with the combination of the two active ingredients is greater than the sum of the effects obtained with each active ingredient taken in isolation.

The combination of (i) betaine or its derivatives and (ii) resveratrol or its derivatives has a synergistic effect on the restoration and / or maintenance of the energy metabolism of the skin. The combination has a synergistic effect on the stimulation of energy metabolism and / or the production of energy by skin cells.

A combination according to the invention, or a composition containing it, is thus useful for stimulating the synthesis of collagen and / or elastin by skin cells.

Indeed, it has been shown, in the context of the present invention, that the synthesis of collagen and elastin by skin cells, such as fibroblasts, is stimulated by resveratrol on the one hand.

Betaine also has a stimulating effect on collagen synthesis by skin cells. The combination of betaine and resveratrol or their derivatives has a synergistic effect of this stimulation.

The invention therefore relates to the use of the combination (or the compositions containing it), for combating the signs of aging of the skin or of the integuments, whether intrinsic or extrinsic.

In addition to wrinkles and fine lines, the appearance of pigment marks, the reduction of the thickness of the skin, its loss of elasticity and its sagging are also changes observed during aging.

The combination, or a composition containing it, will be particularly useful for reducing or preventing skin disorders such as loss of firmness and / or elasticity of the skin, thinning of the skin, wrinkles and fine lines, dull appearance of the complexion, hyperpigmentation of the skin or the heterogeneity of its pigmentation and pigmentation spots.

By skin is meant the skin of the face and / or of the body, the scalp and the mucous membranes or semi-mucous membranes (such as for example the lips). By integuments is meant the hair, body hair, eyelashes, nails, and preferably the hair.

The method according to the invention makes it possible in particular to delay and / or reduce and / or prevent the signs of aging chosen from loss of firmness of the skin, thinning of the skin, wrinkles, fine lines, dull complexion and pigment spots

In the present description, for the intervals expressed between ... and ... or from ... to ..., it is understood that the limits are included.

Resveratrol or its derivatives adapted to the implementation of the invention are in particular chosen from c / s-resveratrol, trans-resveratrol, viniferins, and resveratrol esters, monomers and oligomers, the monomers comprising at least one ester group of formula -O-CO-A, and the oligomers being formed of monomer units joined by carbon-carbon bonds, or ether, and / or of monomers crosslinked by groups -O-CO-R-CO-O with - A representing an alkyl radical of at least two carbon atoms, linear or branched, saturated or unsaturated, an aryl, aralkyl or aralkylene radical, and

- R representing an alkylene radical of 0 to 10 carbon atoms, saturated or unsaturated, and / or 1 arylene radical having 1 to 3 rings and / or a heterocyclic radical, and the diastereoisomers of these units.

Such derivatives are described in application WO 9903816.

The invention relates in particular to compositions characterized in that resveratrol or its derivatives correspond to the following formula

in which

- R 'is hydrogen or the junction point in R ³ or in R ⁴ of another unit,

- R ”is hydrogen or the junction point in R ³ or in R” of another unit,

- R ¹ is a hydrogen, an alcohol function, an ether group or an ester group,

- R ² is a hydrogen, an alcohol function, an ether group or an ester group,

- R ³ represents a hydrogen or the junction point in R ”or R 'of another unit,

- R ⁴ is hydrogen, an alkyl radical, an acyl radical or an R 'junction point of another unit,

- R ⁵ is hydrogen, an alcohol function, an ether group or an ester group.

And the diastereoisomers and regioisomers of these motifs.

By way of example, mention may be made of frans-resveratrol, frans-rhapontine, transdesoxyrhapontine, frans-piceatannol, frans-astringine, frans-pterostilbene, frans-pinosylvine, trans-picéide, frans- e-viniferine, frans-miyabenol C.

In one embodiment of the invention, the compositions are based on resveratrol monomers and / or oligomers comprising at least one -O-CO-A group. In a preferred group, A represents a saturated or unsaturated fatty acid radical.

In the case of an unsaturation, the double bonds are advantageously cis, which corresponds to the most frequent case in natural products. With products obtained more particularly by synthesis or hemisynthesis, the bonds are trans.

Among the fatty acids suitable for the implementation of the invention, mention will be made of butyric, valeric, hexanoic, sorbic, lauric, palmitic, stearic, oleic, linoleic, linolenic, a linolenic, arachidonic, eicosapentaenoic acids; and docosahexaenoic.

C16 and more fatty acids are particularly suitable for cosmetic applications.

In another preferred group, A represents an aryl group, such as the phenyl radical.

In yet another group, A represents an aralkyl or aralkylene group, the alkyl or alkylene group more particularly being in C1 to C8, in particular in C1 to

C4. Mention will be made, in particular of the benzyl or styryl group.

Resveratrol, or 3, 5, 4'-trihydroxystilbene, exists in the cis and trans form. It is generally in the monomer form but also exists as an oligomer comprising up to four monomers. The term resveratrol, in the absence of an indication to the contrary, designates the cis or trans forms of 3, 5, 4'-trihydroxystilbene, and their mixtures. Resveratrol is often associated with Γε-vimfèrine which is a dimer of resveratrol.

Advantageously, the trans form of resveratrol will be used. Other derivatives which can be used are rhapontine, deoxyrhapontine, piceatannol, astringin, pterostilbene, pinosylvine, picideide, and viniferins.

Oligomers which are particularly suitable for the invention comprise, for example, from 2 to 4 monomer units.

According to a particular embodiment, all of the hydroxyl groups of resveratrol are esterified or etherified, the derivative therefore no longer has a free OH function.

Such ethers or esters can in particular be prepared by the process described in application WO 2011/128714 and application WO 99/03816.

According to one embodiment of the invention, resveratrol or its derivatives are used in the form of plant extracts containing it.

They can be obtained from various plant sources. We will mention Vitaceae, Umbelliferae, Myrtaceae, Dipterocarpaceae, Cypéraceae, Gnétaceae, Legumes, Grasses, Seraceae, Haemodoraceae, Musaceae, Polygonaceae, Pinaceae, Cupressaceae, Césalpiniaceae, and Solanaceae.

In particular, the resveratrol and / or the resveratrol derivatives used in the combinations of the invention are extracts from the vine and more especially from vine shoots; these extracts contain monomers, oligomers and / or polymers of units corresponding to the above formula.

Advantageously, resveratrol monomers and / or oligomers are used, as obtained by extraction, using water and / or an organic solvent, from grape vines.

Resveratrol can also be obtained by the use of genetically modified microorganisms from animal tissues or by bioproduction from plants, in particular from suspensions of vine cells.

Betaine, or tri-methyl glycine, can be used in the form of a zwitterion, or in the form of its physiologically acceptable salts or derivatives.

It is understood that in the present text, by betaine or its derivatives is intended to denote betaine, in the form of a zwitterion or one of its physiologically acceptable salts (in particular betaine HCl) and / or one of its physiologically derivatives acceptable; betaine may be present in the compositions according to the invention in any of these forms, and / or their mixtures in all proportions.

The combination useful for the implementation of the invention may contain resveratrol in the form of its various isomers or one of its derivatives as defined in the above isolated or their various mixtures in all proportions.

According to one of the embodiments of the invention, the combination of betaine and resveratrol or one of its derivatives is in the form of a conjugate of the betaine molecule with resveratrol or one of its derivatives.

In particular, resveratrol or its derivative can be linked by a covalent bond to betaine, for example by an ester bond.

The term association in the present description includes such a conjugate resulting from the conjugation between betaine and resveratrol or one of its derivatives.

The combination of (i) resveratrol or one of its derivatives and (ii) betaine has a synergistic effect on the increase in mitochondrial activity, and in particular of the mitochondrial mass, in the skin cells, and more specifically in cutaneous fibroblasts, in particular in fibroblasts in a condition mimicking that of fibroblasts of an elderly subject.

The mitochondrial mass is thus restored to that of a young cell.

The combination according to the invention also has a synergistic effect on the production of energy by the skin cells or its annexes, in particular by human skin fibroblasts.

This effect is observed in particular on the production of ATP by these cells.

We know that the production of ATP is a major source of energy for the various processes of the cell and that its production decreases with age.

Resveratrol (or one of its derivatives) on the one hand and betaine on the other hand, make it possible to increase the production of ATP by fibroblasts. The combination according to the invention has a synergistic effect on increasing the production of ATP.

In particular, on fibroblasts of human skin, the synthesis of intracellular ATP is increased by at least 10%, in particular by at least 18%, or even by at least 20%, compared to the increase which would be expected. by a simple additive effect of each of the two components of the association.

The ATP level can be restored to that of young cells in a healthy subject.

The skin cells can thus recover the metabolism of young cells, and in particular the protein synthesis is restored.

According to one aspect of the invention, resveratrol, or its derivatives, increase the production of collagen and / or elastin by skin cells, in particular by fibroblasts from human skin.

Betaine also increases the production of collagen by skin cells, in particular by human skin fibroblasts.

The combination according to the invention, or the composition containing it, will thus be useful for stimulating the synthesis of collagen and / or elastin in the skin.

Advantageously, the combination according to the invention has a synergistic effect on the increase in the production of collagen by fibroblasts of the skin, in particular of human skin.

Collagen production is therefore equivalent to that of young skin. For example, the level of collagen in a subject to whom the combination or the composition containing it is administered, is restored to the average level of collagen of a younger subject.

According to one of the embodiments of the invention, the ratio between resveratrol and betaine is between 5: 1 and 1: 1000, in particular 5: 1 and 1: 500 and in particular between 1: 1 and 1: 500

The compositions useful for the implementation of the invention contain for example (i) from 0.001 to 10% of resveratrol, in particular from 0.001 to 3% of resveratrol and in particular 0.002 to 1% and (ii) from 0.01 to 10% betaine, in particular from 0.01% to 5% and in particular 0.1 to 5% betaine, the percentages being expressed by weight relative to the total weight of the composition.

In particular, in a composition according to the invention, resveratrol and / or its derivatives may be present at a concentration of 0.002% to 3%, in particular from 0.002 to 0.5% by weight relative to the total weight of the composition.

According to one of the embodiments of the invention, the combination (i) of resveratrol or its derivatives and (ii) of betaine or the composition containing it, is administered orally.

According to another embodiment, the combination (i) of resveratrol or its derivatives and (ii) of betaine or the composition containing it is applied topically to the skin.

These two embodiments can be combined, the combination and / or the composition containing it can be administered orally and topically simultaneously, separately, or sequenced over time.

A composition particularly suitable for the invention contains, in a physiologically, and in particular cosmetically acceptable medium, a synergistic association on the production of collagen by the cutaneous cells of i) resveratrol or one of its derivatives and (ii) betaine ; in such a composition, resveratrol or its derivatives may be present at a concentration of 0.01 to 3% and betaine may be present at a concentration of 0.1 to 10%, the percentages being expressed by weight relative to the total weight of composition.

The compositions according to the invention are preferably cosmetic compositions, or dermatological compositions suitable for application to the skin or the integuments. The composition according to the invention contains the combination of resveratrol or its derivatives and betaine as defined above, and a physiologically acceptable medium.

By physiologically acceptable medium is meant a medium compatible with the skin or the integuments and not causing an undesirable effect when it is brought into contact with the various parts of the body. It can be a medium compatible with oral administration.

It is in particular a cosmetically acceptable medium. This means an environment or excipients well tolerated by the skin and having a pleasant odor and appearance.

For oral administration, the composition of the invention can be in any suitable form, in particular in the form of an oral solution, a syrup, a tablet, a capsule, a dragee. , a capsule, a controlled release hydrogel, or a nutritional food or nutritional supplement. In particular, the combination can be incorporated into any form of food supplement, for example food bars or powders, compacted or not.

For oral use, the composition may thus comprise an ingestible support.

The term “cosmetic product or composition” means a substance or a mixture intended to be brought into contact with the surface parts of the human body or with the teeth and the oral mucous membranes, with a view, exclusively or mainly, of cleaning them, perfuming them, modify their appearance, protect them, keep them in good condition or correct body odors. A cosmetic treatment process within the meaning of the invention has the same objectives.

This composition can be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, a foam. . It can also be in solid form, in particular in the form of a stick. It can be used as a care product and / or as a makeup product and / or hygiene product for the skin or the integuments.

The composition according to the invention can be in all the dosage forms normally used in the cosmetic field, and it can in particular be in the form of an aqueous or oily solution, optionally gelled, of a dispersion of the lotion type, optionally two-phase, of an emulsion obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O), or a triple emulsion (W / O / W or O / W / O) or a vesicular dispersion of ionic and / or nonionic type. These compositions are prepared according to the usual methods.

When the composition used according to the invention is an emulsion, the proportion of the fatty phase can range from 0.5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and coemulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.1 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

As oils which can be used in the invention, mention may be made of hydrocarbons of mineral (mineral oil) or synthetic origin (petrolatum oil, isohexadecane), oils of vegetable origin (apricot almond oil, grapeseed oil liquid fraction of shea butter, avocado oil, soybean oil), oils of animal origin (lanolin), synthetic oils (perhydrosqualene, pentaerythrityl tetraoctanoate), silicone derivatives (cyclopentasiloxane, cyclohexasiloxane, dimethicone and polymers silicone) and fluorinated oils (perfluoropolyethers). Fat can also be used as fatty alcohols (cetyl or stearyl alcohol), fatty acids (stearic acid), waxes (carnauba wax, ozokerite, beeswax), butters, hydrogenated oils.

As emulsifiers and co-emulsifiers which can be used in the invention, mention may, for example, be made of fatty acid and polyethylene glycol esters such as PEG100 stearate and PEG-20 stearate and fatty acid and glycerine esters such as glyceryl stearate, sucrose esters, phospholipids

In a known manner, the composition used according to the invention may also contain the adjuvants usual in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers , filters, screens, pigments, odor absorbers, chelating agents, alcohols and coloring matters. The amounts of these various adjuvants are those conventionally used in the field under consideration, and for example from 0.01 to 20% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase or into the lipid vesicles. In any event, these adjuvants, as well as their proportions, will be chosen so as not to harm the desired properties of the association.

As hydrophilic gelling agents, mention may in particular be made of carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, cite modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.

As fillers, mention may, for example, be made of polyamide (nylon) particles in spherical form or in the form of microfibers; polymethyl methacrylate microspheres; ethylene-acrylate copolymer powders; expanded powders such as hollow microspheres and in particular, microspheres formed from a terpolymer of vinylidene chloride, acrylonitrile and methacrylate and sold under the name EXPANCEL by the company Kemanord Plast; powders of natural organic materials such as starch powders, in particular of corn, wheat or rice starches, crosslinked or not, such as starch powders crosslinked with octenylsuccinate anhydride; silicone resin microbeads such as those sold under the name TOSPEARL by the company Toshiba Silicone; silica; metal oxides such as titanium dioxide or zinc oxide; mica; and their mixtures.

The composition used according to the invention may also contain other active agents, and in particular at least one compound chosen from: antioxidants, hydrating agents; scaling agents; agents improving the barrier function; agents promoting cutaneous microcirculation; depigmenting agents; anti-glycation agents; NO synthase inhibitors; agents stimulating the synthesis of dermal or epidermal macromolecules and / or preventing their degradation; agents stimulating the proliferation of fibroblasts and / or keratinocytes or stimulating the differentiation of keratinocytes; muscle relaxants; tensing agents; anti-pollution and / or anti-radical agents, sun filters, propigmenting agents, anti-inflammatory agents, agents modifying the production of sebum, cooling agents and their mixtures.

As antioxidants, there may be mentioned in particular tocopherol and its esters, in particular tocopherol acetate; ascorbic acid and its derivatives, in particular ascorbyl magnesium phosphate, ascorbyl glucoside and ascorbyl tetraisopalmitate; ferulic acid; serine; ellagic acid, phloretin, chelators, such as BHT, BHA, N, N'-bis (3,4,5-trimethoxybenzyl) ethylenediamine and its salts, hydroxymataisoresinol and mixtures thereof.

In particular, the cosmetic composition according to the invention also contains at least one active agent chosen from vitamin C and its derivatives and vitamin E or its derivatives such as tocopherol acetate.

The additional active agents may be present in the composition according to the invention in a content ranging from 0.001% to 20% by weight relative to the total weight of the composition, preferably from 0.01% to 10%, even more preferably from 0 , 5% to 5% and more preferably from 0.1% to 1% by weight relative to the total weight of the composition.

The subject of the invention is also a cosmetic treatment method comprising a step of application to the skin or the integuments of the combination or compositions according to the invention.

The cosmetic treatment process will therefore aim to prevent or reduce skin signs such as loss of firmness and / or elasticity of the skin, thinning of the skin, wrinkles and fine lines, a dull appearance of the complexion, hyperpigmentation of the skin or the heterogeneity of its pigmentation and age spots.

The compositions and combinations according to the invention may be applied directly to the skin or the integuments or, alternatively, to cosmetic or dermatological supports of the occlusive or non-occlusive type, intended to be applied locally to the skin, such as hydrogel masks, wipes, tissue, or biocellulose.

The application could for example be daily, multi-daily or weekly. It may be continued for several days and / or several weeks, or even longer; it can be continuous or for example continued for 1 to 2 months then resumed after an interruption.

The invention also relates to the use of a combination of (i) resveratrol or one of its derivatives and (ii) betaine or one of its derivatives, as defined in the present text, for the preparation of a cosmetic composition. The composition is suitable for application to the skin or the integuments. The composition advantageously makes it possible to combat the signs linked to the action of free radicals on the skin or the integuments, to restore the energy metabolism of the cell, to stimulate the production of collagen or elastin by the skin, and / or to fight against the signs of aging of the skin.

The invention also relates to a process for the preparation of a cosmetic composition comprising a step in which an effective amount is mixed (i) of resveratrol or one of its derivatives and (ii) of betaine or one of its derivatives, and optionally a physiologically acceptable excipient.

Other characteristics and advantages of the invention are illustrated in the examples which follow.

In these examples, reference is made to the single figure in the appendix.

It represents the effect of resveratrol and betaine, alone or in combination, on the production of ATP by human fibroblasts in culture; the association has a synergistic effect on the increase in ATP production.

EXAMPLE 1 Action of a Combination of Betaine and Resveratrol on the Production of ATP

Human fibroblasts were cultured at 37 ° C. in a humid atmosphere at 5% CO 2, on MEM medium supplemented with glucose, serum and glutamine. A solution containing frans-resveratrol and / or betaine is added to the culture medium.

The primary fibroblast cultures are incubated for 120 min with resveratrol at a final concentration of 1 μΜ, betaine at a concentration of 1 mM or a mixture of the two.

Cell viability is measured after incubation using a fluorescent probe. The concentration of intracellular ATP is measured by means of a chemiluminescence assay; the average of 4 measurements is retained.

The intra-cellular ATP levels are expressed in μΜ ATP per viable cell and the percentage increase in ATP is calculated relative to the ATP level in untreated cells.

The results are illustrated in the appended figure and reported in the following table.

ΑΤΡ (μΜ per cell) Average value Increase (%) Untreated 0.067 Reference Resveratrol 1 μΜ 0.086 28 Betaine 1 mM 0.080 20 Resveratrol 1 μΜ + Betaine 1mM (theoretical) 0.099 48 Resveratrol 1μΜ + Betaine 1mM (measured) 0.112 68

The combination of resveratrol and betaine significantly increases the production of intracellular ATP, which is 68% higher than that of untreated cells.

The activity measured for the resveratrol + betaine combination is more than 20% greater than the theoretical sum of the effects of each compound.

The combination of betaine and resveratrol can combat the decrease in intracellular ATP levels in fibroblasts associated with aging.

EXAMPLE 2 Increase in Mitochondrial Mass by Resveratrol and Betaine

Human fibroblasts were cultured at 37 ° C. in a humid atmosphere at 5% CO 2, on MEM medium supplemented with glucose, serum and glutamine. The cells are treated with a chemical agent (FK866) in the presence or absence of the following compounds: frans-resveratrol and Betaine. The agent FK866 has the effect of reducing the mitochondrial cell mass, thus mimicking one of the signs of aging.

Under these conditions, the capacity of the active agents to increase the mitochondrial mass is evaluated. To do this after 24 hours of treatment, the mitochondrial mass is measured using the Nonyl Acridine Orange probe (NAO, Invitrogen) which fluoresces at 533nm. Labeling with DAPI also makes it possible to measure cell viability. A flow cytometry analysis is performed with a FACS LSRII and the analysis performed with the FlowJo software.

The results are presented in the following tables:

a) Treatment with the chemical agent FK866 decreases the mitochondrial mass of fibroblasts, mimicking certain effects of aging

Mitochondrial mass (Fluorescence units) Average Decrease (%) Basal 1,467.67 Reference FK866 2.5 nM 1325.67 9.68

b) Treatment with Resveratrol, Betaine and their combination protects against the effects of FK866 on mitochondrial mass.

Mitochondrial mass (Fluorescence units) Average Increase (%) FK866 2.5 nM Untreated 1325.67 Reference Betaine 5mM 1,573.67 18.71 Resveratrol 25 μΜ 2,285.00 72.37 Resveratrol 25 μΜ + Betaine 5mM (theoretical) 2,533.00 91.07 Resveratrol 25 μΜ + Betaine 5 mM (experimental) 2,664.67 101.01

EXAMPLE 3 Increase in the Production of Collagen by Resveratrol and Betaine

Skin fibroblasts were cultured for 24 hours with resveratrol, betaine or a mixture of the two compounds.

For gene expression analysis, total RNA was extracted from fibroblast cultures and expression measured by quantitative real-time PCR. The RNA extraction was carried out with an RNeasy Mini Kit (Qiagen). Total RNA was used for cDNA synthesis with the iScript cDNA synthesis Kit (Biorad). The PCR reactions were carried out with the LightCycler® 480 SYBR Green I Master mix (Roche). Each sample was subjected to two PCRs using the appropriate primers listed in the table below. For comparison of relative expressions, the Δ ACt method. The relative expression of the gene of interest is represented by the variation in expression relative to the untreated samples.

Uncomfortable Primer peers Col1A1 GAG GGC CAA GAC GAA GAC ATC (SEQ ID NO: 1) CAG ATC ACG TCA TCG CAC AAC (SEQ ID NO: 2) 18s RNA GAG ACT CTG GCA TGC TAA CTA G (SEQ ID NO: 3) GGA CAT CTA AGG GCA TCA CAG (SEQ ID NO: 4)

The results are reported in the following table:

Relative expression of Col1A1 Average value Increase (%) Untreated 1.00 Reference Resveratrol 4μΜ 1.22 22 Betaine 5mM 1.28 28 Resveratrol 4μΜ + Betaine 5mM (theoretical) 1.50 50 Resveratrol 4μΜ + Betaine 5mM (measured) 1.54 54

Resveratrol and betaine have a synergistic effect on increasing the expression of collagen and 3 genes

Example 4: Composition

Compositions according to the invention are prepared by mixing the constituents of the 5 formulations which follow.

Gel

INCI Name % Aqua QSP 100 Sodium phytate 0.05 Carbomer 0.2 Polyacrylate crosspolymer-6 0.2 Caprylyl glycol 0.3 Palmitoyl grape shoot extract 0.1 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer, Aqua, Sorbitan isostearate 0.2 Tocopherol, 0.3 Betaine 0.5 Perfume 0.1 PH adjuster QSP pH 5.0-5.5

Cream gel

INCI Name % Aqua QSP 100 Tetrasodium EDTA 0.05 Sodium acrylates copolymer, Lecithin 2 sweet almond oil 10 Palmitoyl qrape shoot extract 0.35 Potassium sorbate 0.3 BHT 0.05 Betaine 0.5 Perfume 0.3

Lotion

INCI Name % Aqua QSP 100 Glycerin 10 Resveratrol 0.01 Betaine 1 Alcohol 15

Emulsion

INCI Name % Aqua QSP 100 Butylene glycol 5

Xanthan gum 0.2 Polyacrylate crosspolymer-6 0.5 Cetearyl glucoside, cetearyl alcohol 4 Glyceryl stearate 1 Dicaprylyl ether 5 Butyrospermum parkii 3 Dimethicone 4 Carpyly / capric triglycerides 10 Silica 2 Chlorphenesin 0.2 Benzoate sodium 0.2 Palmitoyl grape shoot extract 0.7 Betaine 0.3 Tocopherol 0.2 Perfume 0.4

Claims (16)

Claims 1. Cosmetic, non-therapeutic use of a combination (i) of resveratrol or one of its derivatives and (ii) of betaine or one of its derivatives, or of a composition containing said association in a physiologically acceptable medium, to fight against the signs of aging of the skin. 2. Use according to claim 1, characterized in that the combination or the composition containing it is administered orally. 3. Use according to claim 1, characterized in that the combination or the composition containing it is applied topically to the skin. 4. Use according to any one of claims 1 to 3, characterized in that the combination (i) of resveratrol or one of its derivatives and (ii) betaine or one of its derivatives, or the composition containing said combination are used to delay and / or reduce and / or prevent the signs of aging chosen from loss of skin firmness, thinning of the skin, wrinkles, fine lines, dull complexion and spots pigmentary. 5. Use according to any one of the preceding claims, for stimulating the synthesis of collagen and / or elastin in the skin. 6. Use according to any one of the preceding claims, characterized in that the combination (i) of resveratrol or one of its derivatives and (ii) of betaine or one of its derivatives has a synergistic effect on energy metabolism and / or energy production by skin cells. 7. Use according to any one of the preceding claims, characterized in that the resveratrol or its derivatives (i) is chosen from c / s-resveratrol, transresveratrol and the resveratrol esters, monomers and oligomers, the monomers comprising at at least one ester group of formula -O-CO-A, and the oligomers being formed of monomer units joined by carbon-carbon bonds, or ether, and / or of monomers crosslinked by groups -O-CO-R-CO- O- with -A representing an alkyl radical of at least two carbon atoms, linear or branched, saturated or unsaturated, an aryl, aralkyl or aralkylene radical, and - R representing an alkylene radical of 0 to 10 carbon atoms, saturated or unsaturated, and / or 1 arylene radical having 1 to 3 rings and / or a heterocyclic radical, and the diastereoisomers of these units. 8. Use according to any one of the preceding claims, characterized in that the association is in the form of a conjugate of betaine with resveratrol or one of its derivatives. 9. A method of cosmetic, non-therapeutic treatment of the signs of aging of the skin, comprising a step of applying, to the skin covering or its appendices, a composition containing a combination (i) of resveratrol or of one its derivatives and (ii) betaine, as defined in one of claims 1 to 8, in a cosmetically acceptable medium. 10. Cosmetic treatment method according to claim 9, characterized in that it makes it possible to delay and / or reduce and / or prevent the signs of aging chosen from the loss of firmness and / or elasticity of the skin, thinning of the skin, wrinkles and fine lines, a dull appearance of the complexion, hyperpigmentation of the skin or the heterogeneity of its pigmentation and pigment spots. 11. Cosmetic treatment method according to any one of claims 9 or 10, characterized in that resveratrol or its derivatives are present in the composition in the form of a plant extract containing it. 12. Cosmetic treatment method according to any one of claims 9 to 11, characterized in that betaine is in the form of one of its physiologically acceptable salts. 13. Cosmetic treatment method according to any one of claims 9 to 12, characterized in that the ratio between resveratrol and betaine is between 5: 1 and 1: 1000. 14. Cosmetic treatment method according to any one of claims 9 to 13, characterized in that the composition contains (i) from 0.001 to 10% of resveratrol and (ii) from 0.01 to 10% of betaine, the percentages being expressed by weight relative to the total weight of the composition. 15. Composition capable of being used according to one of claims 1 to 8, or useful for implementing the method according to one of claims 9 to 14, characterized in that it contains, in a physiologically acceptable medium , a synergistic association on the production of collagen by the cutaneous cells of i) resveratrol or one of its derivatives and (ii) betaine, resveratrol or its derivatives being present at a concentration of 0.002 to 3% and betaine being present at a concentration of 0.1 to 10%, the percentages 5 being expressed by weight relative to the total weight of the composition. 16. Composition according to claim 15, characterized in that the medium is a cosmetically acceptable medium and in that it also contains at least one active agent chosen from antioxidants, hydrating agents, desquamating agents, agents improving the barrier function, depigmenting agents and agents promoting cutaneous microcirculation. 1/1 [ΑΤΡ] (μΜ / cell) 0.16 0.14 0.12 0.1 0.08 0.06 0.04 0.02 UNTREATED RESV 1μΜ BETAINE 1 mM RESVIpM + BETAINE 1mM (theoretical) RESVIpM + BETAINE 1mM (experimental) sequence listing FR_ST25 SEQUENCE LISTING <110> CAUDALIE IP PRESIDENT AND FELLOWS OF HARVARD COLLEGE <120> Use of a resveratrol-based combination to combat the signs of aging skin <130> BR 85229 <160> 4 <170> Patentln version 3.5 <210> <211> <212> <213> 1 21 DNA Artificial Sequence <220> <223> primer sense CollAl <400> 1 gagggccaag acgaagacat c 21 <210> <211> <212> <213> 2 21 DNA Artificial Sequence <220> <223> primer reverse CollAl <400> 2 cagatcacgt catcgcacaa c 21 <210> <211> <212> <213> 3 22 DNA Artificial Sequence <220> <223> primer meaning RNA18S <400> 3 gagactctgg catgctaact ag 22 <210> <211> <212> <213> 4 21 DNA Artificial Sequence <220> <223> RNA18S reverse primer <400> 4 ggacatctaa gggcatcaca g 21 Pge p